Project Summary/Abstract This resubmission for a Mentored Patient-Oriented Research Career Development Award (K23) is from a neurologist specializing in movement disorders. The integrated career development and research plan are focused on the development of markers of vulnerability to cognitive decline in Parkinson?s disease (PD) and use their use to predict cognitive decline following Deep Brain Stimulation (DBS) in PD, using cognitive performance combined with PET imaging of the ?4?2-nicotinic acetylcholine receptor (?4?2-AChR). The overarching hypothesis is that cognitive dysfunction localizing to specific cortical regions, and decreased ?4?2- AChR availability in these regions, will predict cognitive impairment following DBS surgery. The research project is motivated by the increasing awareness of cognitive impairment as a disabling symptom of PD as motor symptoms are treated earlier with advances in therapies. The lack of reliable clinical markers for impending cognitive impairment in surgical decision-making exposes some patients to excessive ?cognitive risk? by undergoing DBS surgery while allowing other good candidates to go untreated with DBS. To this end, the aims are to 1) measure ?4?2-AChR in PD patients and controls in regions involved in PD-related cognitive impairment, 2) measure associations between ?4?2-AChR and cognitive impairment in PD, and 3) measure associations between baseline ?4?2-AChR and subsequent cognitive decline following DBS surgery. The research plan is complemented by a career development plan with the following specific short-term training goals focused on: 1) the application, analysis and interpretation of PET imaging, 2) selection, analysis, and interpretation of cognitive evaluations, 3) a comprehensive understanding of cognitive changes related to DBS, 4) advanced training in biostatics, and 5) developing multidisciplinary collaboration as a translational researcher. The candidate will be mentored directly by senior faculty with expertise in pathophysiology research in PD, molecular imaging and cognition in neurodegenerative disease and PD, motor and non-motor effects of DBS in PD and biostatistics and will participate in complementary formal coursework and external training programs. Completion of the research and training objectives will advance the career of a junior investigator toward developing an independent research program focused on developing neuropsychological and molecular imaging risk factors for cognitive decline following functional neurosurgery in PD patients, an increasingly common procedure and prevalent disease. Understanding the mechanistic role of the nicotinic cholinergic system in rapid changes in cognitive function following invasive brain procedures will inform the design of an R01 proposal to validate the use of these markers in the prediction of impending cognitive decline in PD following invasive brain procedures. The results will also have implications for the development of future therapies to mitigate cognitive dysfunction in PD based on the nicotinic cholinergic system.